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A Genomic Survey of Melanoma

Researchers have performed the first comprehensive genomic analysis of melanoma, the deadliest form of skin cancer. The findings provide a better basis for understanding melanoma and for developing new treatment strategies.

Melanoma is the most serious form of skin cancer. Its incidence is increasing faster than any other cancer. A major cause is thought to be overexposure to the sun. The sun’s ultraviolet radiation can damage the DNA in skin cells, causing genetic changes that may lead to cancer. Some candidate genes have been linked to melanoma, but to date no comprehensive analysis of melanoma genetics had been performed.

A team of researchers led by Dr. Yardena Samuels of NIH’s National Human Genome Research Institute (NHGRI) set out to identify genetic changes that can lead to melanoma. Their strategy was to sequence exons—the parts of the genome that contain information needed to produce proteins, the body’s building blocks. The complete set of exons, the “exome,” makes up just a small fraction of the human genome—1 to 2%.

The researchers started with 14 samples of metastatic melanoma tumors and matching blood samples from a collection maintained at NIH’s National Cancer Institute (NCI). Metastatic melanoma is the advanced stage of the disease when cells have the highest accumulation of gene mutations. The study appeared in the April 15, 2011, early online issue of Nature Genetics.

The scientists first differentiated mutations that occur sporadically (somatic mutations) from inherited mutations. They did this by comparing mutations in tumor cells to those in blood samples from the same person. This gave them a set of thousands of somatic mutations. They used a variety of methods to eliminate mutations with no functional role, called passenger mutations. The researchers then applied 2 different screens to the resulting collection. Mutations of interest were confirmed in additional patients.

In one approach, the team searched for mutations that occurred in multiple patients. They found mutations in the gene BRAF, previously implicated in melanoma, and in 9 other genes. Mutations in a gene called TRRAP occurred at the same position in 6 separate people with melanoma.

To test whether TRRAP is an oncogene—a gene that can prevent normal cell death and cause cancer—the researchers disrupted TRRAP in melanoma cells. As expected for an oncogene, disruption of TRRAP caused an increase in cell death.

In another approach, the researchers looked for genes with a higher-than-expected mutation rate. Of the 16 identified genes, only BRAF had previously been implicated in melanoma. Another, GRIN2A, is one of the most highly mutated genes associated with melanoma to date. The identification of GRIN2A, along with other data from the study, implicate the glutamate signaling pathway in melanoma.

“This study is an example of the vital utility of preserving high-quality tumor samples that include clinical information,” says coauthor Dr. Steven Rosenberg of NCI. “Furthermore, it is a powerful example of the importance of bridging basic science and clinical medicine.”